Process for the preparation of 21-phosphate steroids



United States Patent 3,487,077 PROCESS FOR THE PREPARATION OF ZI-PHOSPHATE STEROIDS Norman L. Wendler, Summit, and Harry L. Slates, Florham Park, N.J., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey N0 Drawing. Continuation of application Ser. No.

453,173, May 4, 1965. This application Feb. 16,

1968, Ser. No. 706,194

Int. Cl. C07c 167/28, 173/00; C07f 9/08 U.S. Cl. 260-23955 Claims ABSTRACT OF THE DISCLOSURE The invention disclosed herein relates to and has for its object an improved process for the preparation of 21- phosphate steroids of the substituted pregnane series and alkali metal salts thereof by direct phosphorylation of the corresponding 2l-hydroxy steroid using pyrophosphoryl chloride as the phosphorylating agent.

This is a continuation of application Ser. No. 453,173, filed May 4, 1965, now abandoned.

According to the improved process of this invention, the 21-phosphate steroids of the substituted pregnane series are prepared by the phosphorylation of 2l-hydroxy steroids of the substituted pregnane series. Any 21-hydroxy steroid of the substituted pregnane series may be phosphorylated according to the process of this invention which does not have an unprotected hydroxyl group on a carbon atom of the ring system or on a side-chain carbon atom, except that a 21-hydroxy steroid with a hydroxyl group in the ll-position may be phosphorylated according to the process of this invention to give a 21- phosphate steroid if a halogen or alkyl group is at the 9-position. Phosphorylation of a 2l-hydroxy steroid with an unprotected hydroxyl group on a carbon atom of the ring system usually brings about the removal of a molecule of water and double bond formation it a hydrogen is present on the carbon atom adjacent to the carbon atom on which the hydroxyl is attached. However, a 9-halo or 9-alkyl-1l,21-dihydroxy steroid may be phosphorylated to give a 11,21-dihydroxy steroid 2l-phosphate according to the process of this invention without the removal of a molecule of water and double bond formation even if hydrogen is present on the 12-position. Hydroxyl groups on a carbon of the ring system may be protected according to any known means such as ester or ether formation to provide alkoxy, aralkoxy, benzoxy or substituted benzoxy groups and acyloxy, benzoyloxy or substituted benzoyloxy groups, and two adjacent hydroxyl groups may be protected by acetal or ketal formation.

Some 21-phosphate steroids of the substituted pregnane series which may be prepared by the process of this invention, have structural Formulas A, B, and C.

3,487,077 Patented Dec. 30, 1969 wherein R is hydrogen, acyl, alkyl, aralkyl, cycloalkyl, aryl, a heterocyclic nucleus, or substituted derivatives thereof, R is methylene, hydroxy methylene or carbonyl, X is hydrogen, halogen or lower alkyl, but when R is hydroxyl, X is halogen or lower alkyl, X is hydrogen, methyl, flnoro or chloro, P and Q are each hydrogen, alkyl, halo-lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyelic aryl lower alkyl, monocyclic heterocyelic or monocyclic heterocyclic lower alkyl; or together with the carbon atom to which they are joined, P and Q are cycloalkyl or monocyclic heterocyclic:

OOH

wherein the 1,2-position is saturated or double-bonded, R is hydrogen or methyl, R is methylene, hydroxymethylene, or carbonyl, R is hydrogen or lower alkyl, R is lower alkyl, X is hydrogen, halogen or lower alkyl, and when X is hydrogen R is methylene or carbonyl, X is hydrogen, lower alkyl, or halogen, preferably fluoro, Y is methylene, carbonyl or thiocarbonyl, Z is hydrogen or acyloxy, Z is hydrogen, halogen, trifluoromethyl or lower alkyl, or wherein Z and Z are together in which P and Q have the same significance as in structural Formulas A and B.

In all of the compounds of the A, B, and C structural formulas, a double bond may be present at the A position.

The 2l-phosphate steroids of the substituted pregnane series having structural Formulas A, B and C are prepared by direct phosphorylation of the corresponding 21- hydroxy steroids of the substituted pregnane series with pyrophosphoryl chloride.

In the direct phosphorylation an excess of pyrophosphoryl chloride is used which acts as a solvent for the 21- hydroxy steroid which is to be phosphorylated. The solution of ZI-hydroxy steroid in pyrophosphoryl chloride is protected from moisture and stirred at a temperature from about 40 C. to about 20 C. until all the 2]- hydroxy steroid is in solution and for a short time thereafter during which the temperature of the reaction mixture is maintained within the same range. The reaction mixture is then slowly added to an amount of vigorously stirred water sufl'icient to decompose all the excess pyrophosphoryl chloride and convert the intermediate 21-dichlorophosphate steroid to 21-dihydrogen phosphate steroid and stirred for a short time after addition is complete to make certain all excess pyrophosphoryl chloride is decomposed and the 21-dichlorophosphate steroid is converted to the ZI-dihydrogen phosphate steroid. If the 21-dihydrogen phosphate steroid is negligibly soluble in Water, the precipitate of 21-dihydrogen phosphate steroid, which is formed upon addition of the reaction mixture to water, is removed by filtration, and dried under reduced pressure. However, if the 21-dihydrogen phosphate steroid is appreciably soluble in Water, it may be isolated by extraction with a suitable solvent, such as chloroform or ether, or by ion exchange chromatography.

Both monoand di-alkali metal salts of the 21-phosphate steroids of structural Formulas A, B and C may be obtained by treatment of such compounds With an alkali metal compound, e.g., an alkali metal hydroxide,

such as sodium hydroxide, potassium hydroxide, or the like, or with an alkali metal carbonate such as sodium carbonate, potassium carbonate, or the like.

The 21-phosphate steroids of the substituted pregnane series having structural Formulas A, B and C and alkali metal salts thereof have extremely high anti-inflammatory activity and are particularly suitable for use in preparing aqueous solutions and formulations for topical, intravenous and intramuscular application because of their high order of solubility in Water.

Among the suitable starting 21-hydroxy steroids of the substituted pregnane series utilizable for the production of the compounds of the structural Formulas A, B and C in the process of this invention may be mentioned:

16a,17a-(butylidene)-6-fluorotriamcinolone,

16oz, 17oc- 3 '-pentylidene) -6ot-fluorotriamcinolone,

16a,17a-cyclohexylidene-6a-fluor0triamcinol0ne,

16oz, 17a-isopropylidene-6a-fiuoro-9a-methyl-16a-hydroxyprednisolone,

16a,17a-isopropylidene-6a,9a-difluoro- 16u-hydroxydrocortisone,

1 6a,17a-isopropylidene-6a,9oz-difiuoro-16ahydroxyprednisolone,

16a,17a-chloroisopropylidene-6a,9a-difluoro-16ahyd roxyprednisolone,

16a,17a-isopropylidene-6a-fluorotriamcinolone,

16a,17a-isopropylidene-6u,9o-difluoro-12a-methyll6a-hydroxyhydro cortisone,

9a-fluoro-11,8,16a,2l-tetrahydroxy-20-oxo-2'-(pfiuorophenyl) -4-pregneno-[3,2-c]pyrazole-16a,17aacetonide,

6a,9a-difluoro-11 3,16u,17u,21-tetrahydroxy-20-oxo-4- pregneno-[3,2-c]pyrazole-16a,17a-acetonide,

9oz-fl1101'O-1 1,8,16a,17u,21-tetrahydroxy-6a-methyl-20-oxo- 4-pregneno- [3 ,2-c]pyrazole-16a,17a-acetonide,

9a-fluoro-1 15,1601,17a,21-tetrahydroxy-6u-methyl-ZO- oxo-2-phenyl-4-pregneno-[3,2-c]pyrazole-16a,17aacetonide,

9a-fiuoro-1 15,16a,17a,21-tetrahydroxy-6u-methyl-20- oxo-2'- (p-fluorophenyl) -4-pregneno- 3 ,2-c] pyrazole- 160:,170t-21C6110Did6,

6,9a-difiuoro-1 1,8,16a,1711,21-tetrahydroxy-2O-oxo-4,6-

pregnadiene- [3,2-c1pyrazole- 16a, 17OL-aC6tOI1ld,

6,9oc-difllrO-l 15,16a,17a,21-tetrahydroxy-20-oxo-2'- phenyl-4,6-pregnadieno-[3,2-c]pyrazole-16a,17uacetonide,

(p-fluorophenyl) -4,6-pregnadieno- 3 ,2-c] pyrazoleoxo-2phenyl-4,6-pregnadieno-[ 3,2-c]pyrazole-1 60a, 17aacetonide, 9a-fluoro-11fl,16a,17a,21-tetrahydroxy-6-methy1-20-oxo- 2- (p-fluorophenyl -4,6-pregnadieno- 3,2-c] pyrazole- 1 7u-3C61ZOI1id6, 9a-fluoro-1 15,16a,l711,21-tetrahydroxy-2O-oxo-2-phenylpregnadieno- 3 ,2-c]pyrazole-16a,Wot-acetonide, 9a-fluoro-115,16a,1704,21-tetrahydroxy-20-oxo-2-phenyl- 4,6-pregnadieno- 3 ,2-c]pyrazo1e-16a,Uri-acetonide, 9a-fiu0ro-11B,16a,17a,2l-tetrahydroxy-ZO-oxo-Z'-(pfluorophenyl) -4,6-pregnadieno- 3 ,2-c]pyrazole-16a,17a-

acetonide, 6-fluoro-16u,17a,21-trihydroxy-20=oxo-4,6-pregnadieno- [3,2-c] pyrazole- 1 60a, 1 7(1-aCet0I1idC, 6-fluoro-16a,1711,21-trihydroxy-2O-oxo-2'-phenyl-4,6- pregnadieno- 3 ,2-c]pyrazole-16a,17a-acetonide, 6-fluoro-16u,17a,21-trihydroxy-20-oxo-2'- (p-fluorophenyl) -4,6-pregnadieno- [3 ,Z-c] pyrazole- 16, Nix-acetonide, 16a,17a,21-trihydroxy-6-methyl-20-oxo-4,6-pregnadieno- [3,2-c]pyrazole-16a, L-3C8t011id6, 16a,17a,21-trihydroxy-6-methyl-20-oxo-2-phenyl-4,6

pregnadieno-[3,2-c]pyrazole-16a,Nix-acetonide, 16a,17a,21-trihydroXy-6-methyl-2O-oxo-2'- (p-fiuorophenyl -4,6-pregnadieno- 3 ,2-c] pyrazole- 16a, 17a-aCClZ0l1ide, 16a,17x,21-tril1ydroxy-2O-oXo-4,6-pregnadieno- [3 ,2-c]pyrazole-16u, 17OL-aCCtOl1id6, 16a,17a,21-trihydroxy-20-0x0-2'-phenyl-4,6-pregnadieno- [3 ,Z-c] pyrazole-16a,Not-acetonide, 16a,17a,21-trihydroxy-20-oxo-2'-(p-fiuorophenyl)-4,6-

pregnadieno- [3,2-c] pyrazo1e-16a, I7OL-BCCtOI1idC, 16a,17a,21-trihydroxy-20-oxo-4-pregneno- [3 ,2-c]pyrazole-16a,Nix-acetonide, 16a,17u,21-trihydroxy-20-oxo-2-pheny1-4-pregneno- [3,2-c1pyrazole-16a,17u-acetonide, 160,17a,21-trihydroxy-20-oXo-2'-(p-fluorophenyl)-4- pregneno- [3,2-c]pyrazole-l6a,17a-acetonide, 16a,1711,21-trihydroxy-6a-methyl-20 -oxo-2-phenyl- 4-pregneno- [3 ,2-c] pyrazole-16a, Wot-acetonide, 16a,17a,21-trihydroxy-6a-methyl-20-oxo-2- (p-fiuorophenyl)-4-pregneno-[3,2-c1pyrazole- 16a,17a-acetonide, 16u,17a,21-trihydroxy-6a-methyl-20 -oxo-4-pregneno- [3,2-c]pyrazole-16a, Hot-acetonide, 6-fluoro-16a,17a,21-trihydroxy-11,20-dioxo-4,6

pregnadieno- [3 ,2-c]pyrazole-16a,17a-acetonide, 6-fluoro-16a,17m,21-trihydroxy-11,20'dioxo-2-phenyl- 4, 6-pregnadieno- 3,2-c] pyrazole- 1 6oz, 17OL-8C6t0l'lld6, 6-fluoro-16a,17a,21-trihydroxy-11,20-dioxo-2' (p-fiuorophenyl -4,6-pregnadieno- 3,2-c] pyrazole- 1 611,1702-3C6t011idfi, 16a,170:,21-trihydroxy-6-methyl-1 1,20-dioxo-4,6-

pregnadieno- 3,2-c] pyrazole-16u, 17tZ-aCtOI1id6, 16cc,17a,21-trihydroxy-6-methyl-11,20-di0xo-2'-pheny1- 4,6-pregnadieno- 3 ,2-c]pyrazole-16a, Not-acetonide, 16a,170;,21-trihydroxy-6-methyl-1 1,20-dioxo-2' (p-fluorophenyl -4,6-pregnadieno- 3 ,2-c] pyrazole- 1 6oz,l7oc-8.Ct011id, 16a,17a,21-trihydroxy-1 1,20 -dioxo-4,6-pregnadieno [3,2-c]pyrazole-16a, Hot-acetonide, 16u,17a,21-trihydroxy-11,20-dioxo-2 phenyl-4,6-

pregnadieno-[3,2-c]pyrazole-16a,17a-acetonide, 16oz, 17a,2 1 -trihydroxy-1 1,20-dioxo-2'- (p-fluorophenyl 4,6-pregnadieno- 3 ,Z-c] pyrazole- 1 6a, Not-acetonide, 160:, 17 11,2 l-trihydroxy-l 1,20-dioxo-4-pregneno- 3 ,2-c]

pyrazole- 1 6a, Hot-acetonide, 16a, 1 70,2 l-trihydroxy-l 1,20-dioxo-2'-phenyl-4-pregneno- [3 ,Z-c] pyrazole- 1 60, Uni-acetonide, 16a, 1 7a,2 l-trihydroxy-l 1,20-dioxo-2- (p-fluorophenyl) The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

EXAMPLE 1 Preparation of 16a-17a-(2-butylidene)-6ot-fiuorotriam cinalone 2l-phosphate and potassium salt 0.5 g. of 16a-17a-(2'-buty1idene)-6a-fluorotriamcinalone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at C. during addition and for twenty minutes after addition is complete. The reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The residue is 16oc,l7a-(2'- butylidene)-6a-fluorotriamcinalone 21-phosphate in substantially pure form.

The 16a-17a-(2-butylidene)-6a-fluorotriamcinalone 21- phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 16a17a-(2'-butylidene)-6rx-fluoro-triamcinalone 21-phosphate.

EXAMPLE 2 Preparation of 16a,17a-(3'-pentylidene)-6a-fluoro-triarncinalone 2l-phosphate and potassium salt 0.5 g. of 16a,l7a (3 pentylidene)-6a-fiuor0-triamcinalone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addition is complete. The reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of choloform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The residue is 16u,17a-(3'- pentylidene) 6a fluoro-triamcinalone 21-phosphate in substantially pure form.

The 16a 17a-(3'-pentylidene)-6a-fluoro-triamcinalone 21-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of l6u-17ot-(3- pentylidene)-6a-fiuoro-triamcinalone 21 phosphate.

EXAMPLE 3 Preparation of 16a,l7a-cyclohexylidene-6ot-fluoro-triamcinalone 21-phosphate and potassium salt 0.5 g. of 16a,l7u-cyclohexylidene-6a-fluoro-triamcinalone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addition is complete. The reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The residue is l6a,l7a-cyclohexylidene- 6a-fluoro-triamcinalone 21-phosphate in substantially pure form.

The l6a,17rx cyclohexylidene-6a-fluoro-triamcinalone Zl-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 16u-17a-cyclohexylidene-6u-fluoro-triamcinalone 21-phosphate.

EXAMPLE 4 Preparation of 16a,17a-isopropylidene-6a-fluoro-9amethyl-l6ot-hydroxyprednisolone 21-phosphate and potassium salt 0.5 g. of 16a,17a-isopropylidene-6a-fluoro-9owmethyl- 16a-hydroxyprednisolone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addition is complete. The reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The residue is 160:,1771- isopropylidene-6a-fiuoro-9a-methyl 16a hydroxyprednisolone 21-phosphate in substantially pure form.

The 16a,l7u isopropylidene-6a-fluoro-9u-methyl-16ahy-droxyprednisolone 21-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. Thesolution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of l6a,17 x isopropylidene-6ot-flu0ro-9a-methyl-l6m-hY' droxyprednisolone 21-phosphate.

EXAMPLE 5 Preparation of 16a,17a-isopropylidene-6a,9u-difiuoro-16ahydroxyhydrocortisone 2l-phosphate and potassium salt 0.5 g. of 16a,17a-isopropylidene-6a,9udifiuoro-l6a-hydroxyhydrocortisone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addition is complete. The reaction mixture is then clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation I under reduced pressure. The residue is l6a,17a-isopropylidene-6a,9a-difluoro-l6a-hydroxyhydrocortisone 21-phosphate in substantially pure form.

The l6a,17a-isopropylidene 604,9u difluoro-l6u-hy droxyhydrocortisone 21-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of l6ot,l7a-isopropylidene 6a,9a difluoro-l6a-hydroxyhydrocortisone 21-phosphate.

EXAMPLE 6 Preparation of 16a,17u-isopropylidene-6a,9m-difluoro-16ahydroprednisolone 2l-phosphate and potassium salt 0.5 g. of 16a,17a-isopropylidene-6ot,9a-difluorol6a-hydroprednisolone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addition is complete. The reaction mixture is then a clear solution and is slowly added to ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml.

portions of chloroform. The chloroform extracts are com bined and the chloroform is removed by distillation under pressure. The residue is 16a,l7ot-isopropylidene-6ix,9a-difiuoro-16ot-hydroprednisolone 21-phosphate in substantially pure form.

The 1611, l7wisopropylidene-6a,9cx-difiuoro-l6u-hydroprednisolone 21-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 16a,17a-isopropylidenc 60,9OL difiuoro-l6u-hydroprednisolone 21-phosphate.

EXAMPLE 7 Preparation of 16a,l71x-chloro-isopropylidene-6u,9ot-

difiuoro 16cc hydroxyprednisolone 2l-phosphate and potassium salt 0.5 g. of l6a,l7u-chloro-isopropylidene-6a,9ot-difluoro- 16a-hydroxyprednisolone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at C. during addition and for twenty minutes after addition is complete. The reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The reisdue is 160:, l7u-chloro-isopropylidene-6a,9 t-difiuoro 160a hydroxyprednisolone 21-phosphate in substantially pure form.

The 16a,17a-chloro-isopropylidene-6a,9a-difiuoro-16ahyd-roxyprednisolone 21-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of l6ot,l7ot chloro-isopropylidene-6a,9rxdifluoro-l6a-hydroxyprednisolone 21-phosphate.

EXAMPLE 8 Preparation of 16:1,l7ot isopropylidene 60c fluorotriamcinolone 2l-phosphate and potassium salt 0.5 g. of 16a,l7a-isopropylidene-6a-fluorotriamcinolone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addi tion is complete. The reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The residue is 16a,17a-isopropylidene- 6u-fluorotriamcinolone 2l-phosphate in substantially pure form.

The 16a,17a-isopropylidene-6a-fluoro-triamcinolone 21- phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 16a,17a-isopropylidene-6a-fluorotriamcinolone 21-phosphate.

EXAMPLE 9 Preparation of 1611,17a isopropylidene-6a,9a-difiuoro- 12a-methyl-16u-hydroxyhydrocortisone 21 phosphate and potassium salt 0.5 g. of 16a,l7u-isopropylidene-6u,9a-difluoro-12amethyl-16a-hydroxyhydrocortisone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addition is complete. The

reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The residue is 16a,l7u-isopropylidene-6a,9a-difluoro-l2a-methyl 16ahydroxyhydrocortisone 2l-phosphate in substantially pure form.

The 1 601, l 7OL-lSOPl'OPYlldEI1fl-6OL,9tZ-dlflll0f0-12OC-methy1- l6a-hydroxyhydrocortisone ll-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of l6a,l7a-isopropylidene-6a,9a-difluoro 12arnethyl-l 6a-hydroxyhydrocortisone 2 l-phosphate.

EXAMPLE 10 Preparation of a fiuoro-llB,16a,l7a,21 tetrahydroxy- 20-oxo-4-pregneno-[3,2-c]pyrazole-l6a,17a acetonide 2l-phosphate and sodium salt 0.5 g. of 9oc-flUO1O-llfi,l6ot,l7ot,2l tetrahydroxy-20- oxo-4-pregneno-[3,2-c]pyrazole 16a,17u acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the tem perature is allowed to rise to room temperature. The precipitate of 9a-fluOIO-l1fl,l6oc,l7a, 21-tetrahydroxy-20- oxo-4-pregneno-[3,2-c1pyrazole 16a,17et acetonide 21- phosphate is removed by filtration and dried under reduced pressure at C.

The 9OL-flllOI'O 11/3,16a,17a,2l-tetrahydroxy-20-oxo-4- pregneno-[3,2-c]pyrazole-16a,flat-acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 9a-fluoro llfi,l6a,l7a,2l-tetrahydroxy 20 oxo-4-pregneno [3,2-c]pyraz0le-16a,17aacetonide 2l-phosphate.

EXAMPLE 11 Preparation of 611,90: difluoro-l1fl,16u,17a,21-tetrahyhydroxy-20-oxo 2 (p-fiuorophenyl) 4 pregneno- [3,2-C]pYT2lZOl-16OL,170L-aC6tOIlld6 21 phosphate and sodium salt 0.5 g. of 60,9cc-dlfillOIO-11,3,160c,170c,21 tetrahydroxy- 20 oxo 2' (p-fluorophenyl)-4pregneno-[3,2-c]pyrazole-16u,17a-acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 6a,9a-difil101"0 llfi,l6a,17u,2l-tetrahydroxy 20 oxo 2' (p-fluorophenyl) 4 pregneno [3,2-c]pyrazole-16u,17a-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 60,9ot-difi110lO-llf3,l6ot,l7ct,21 tetrahydroxy 20- oxo 2 (p-fluorophenyl) 4 pregneno-[3,2-c]pyrazole l6a,17u acetonide 21 phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 606,90L-Cllfill0lO-115,16,1711,21-11611311Yd10XY 20- oxo 2(p-fluorophenyl) 4 pregneno-[3,2-c]pyrazole- :,170c-Z1C6t011id6 21-ph0sphate.

9 EXAMPLE 12 9oz fiuoro 115,16a,17a,21 tetrahydroxy 6a methyl- 20 oxo 4 pregneno [3,2 c]pyrazole 16a,17aacetonide 21-phosphate and sodium salt 0.5 g. of 9'a-fluoro-115,1604,17u,21-tetrahydroxy-6amethyl 20 oxo 4 pregneno [3,2 c]pyrazole 16a, 17a-3C6t0nid6 is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold Water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 9otflllOIO-11 3,16a,l7a,21- tetrahydroxy 6oz methyl 20 oxo 4 pregneno [3,2- c]pyrazole-16a,Not-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 91x fiuoro 11fi,l6a,17a,21 tetrahydroxy 6amethyl 20 0x0 4 pregneno [3,2 c]pyrazole 16a, 17a-acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 9a-fluoro-11B,16ot, 170:,21 tetrahydroxy 6a methyl 20 oxo 4 pregneno [3,2-c]pyrazole-16a,17a-acetonide 21-phosphate.

EXAMPLE 13 Preparation of 6-fiuoro-l6a,17u,21-trihydroxy-20-oxo-2- (p fluorophenyl) 4,6 pregnadieno [3,2 c]pyrazole-16u,17a-acetonide 21-phosphate and sodium salt 0.5 g. of 6-fiuoro-16u,17a,2l-trihydroxy-20-oxo-2-(pfluorophenyl) 4,6 pregnadieno [3,2 c]pyrazole 16a, 17OL-aC6tOIlld6 is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold Water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 6-fluoro-16a,17a,21-trihydroxy-20- 0x0 2' (p fluorophenyl) 4,6 pregnadieno [3,2- c]pyrazole-16a,17c-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 6 fiuoro 16cc,17a,21 trihydroxy 20 oxo (pfluorophenyl) 4,6 pregnadieno [3,2 c]pyrazole 16a, Nor-acetonide 2l-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 6-fl110r0-16a,l7a,21- trihydroxy 20 oxo(p fluorophenyl) 4,6 pregnadieno [3,2 c]pyrazole 16a,17oz acetonide 21-phosphate.

EXAMPLE 14 Preparation of 16a,170:,21-trihydroxy-6-methyl-20-oxo-4, 6 pregnadieno [3,2 c]pyrazole 160a, 170a acetonide 21-phosphate and sodium salt 0.5 g. of 16a,17a,21-tIihYdl'OXY-6-methyl-20-OX0-4,6- pregnadieno [3,2 c]pyrazole 16u,17u acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 16a,17 x,2l-trihydroxy-6-methyl-20-oxo-4,6- pregnadieno [3,2 c]pyrazole 16u,17u acetonide 21- phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 16a,17ot,21 trihydroxy 6 methyl 20 oxo- 4,6 pregnadieno [3,2 c]pyrazole l6 x,17a acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 16u,17a,21-trihydroxy-6- methyl 20 oxo 4,6 pregnadieno [3,2 c]pyrazole- 16a,17a-acetonide 21-phosphate.

EXAMPLE 15 Preparation of 16a,17a,21-trihydroxy-20-oxo-4,6-pregnadieno [3,2 c]pyrazole 160:,17a acetonide 21-phosphate and sodium salt 0.5 g. of 16a,1711,21-trihydroxy-20-oxo-4,G-pregnadieno- [3,2-C1PYIZIZOl6-16ot,17ot-3.Ct011ld6 is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 16a,l7a, 21 trihydroxy 20 oxo 4,6 pregnadieno [3,2 c] pyrazole-16a,17a-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at C.

The 16a,17a,21 trihydroxy 20 oxo 4,6 pregnadieno [3,2 c]pyrazole 16a,17a acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 16a,17a,21-trihydroxy-20-oxo-4,6-pregnadieno [3,2 c]pyrazole 1604,1700 acetonide 21-phosphate.

EXAMPLE 16 Preparation of 16a,17a,21-trihydroxy-20 oxo-2-(p-fluorophenyl) 4,6 pregnadieno- [3,2-c]pyrazole-16a,17aacetonide 21-phosphate and sodium salt 0.5 g. of 16a,17u,21-trihydroxy 20 oxo-2-(p-fluorophenyl) 4,6 pregnadieno-[3,2-c]pyrazole-16a,17a-acetonide is added with stirring to 3.0 ml. of pyrophosphonrl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 16a,17a,21-trihydroxy-20-oxo-2- (p-fluorophenyl) 4,6 pregnadieno-[3,2-c]pyrazole-16u,

EXAMPLE 17 Preparation of 16a,17a,21-trihydroxy-20-oxo-4-pregneno- [3,2-c] pyrazole 16ot,17oc acetonide 21-phosphate and sodium salt 0.5 g. of 16a,17a,21-trihydroxy 20 oxo-4-pregneno- [3,2-c]pyrazole-16a,Hot-acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 16a,17a,21-trihydroxy 20 oxo-4-pregneno [3,2-c]pyrazole-16a,17aacetonide 2l-phosphate is removed by filtration and dried under reduced pressure .at 100 C.

The 16a,17u,21-trihydroxy-20-oxo-4-pregneno- [3,2-c] pyrazole-16a,17a-acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 160:,17 ail-trihydroxy 20 oxo-4-pregneno-[3,2-c1pyrazole-l6a,l7a-acetonide 21-phosphate.

EXAMPLE 18 Preparation of 16a,17a,21-trihydroxy-6a-methyl-2-oxo-4- pregneno[3,2-c]pyrazole 160:,17a acetonide 21-phosphate and sodium salt 0.5 g. of 16a,17a,21-trihydroxy-6u-methyl-2-ox0-4-pregneno-[3,2-c]pyra-zole-l6a,l7a-acetonide is added with stir ring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 16a,170:,2l-trihydroxy-6a-methyl-2-oxo-4pregneno [3,2- c]pyrazole-l6a,l7ot-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 16a,l7u,21-trihydroxy 60c methyl-2-oxo--4-pregneno-[3,2-c]pyrazole 16a,17a acetonide 2l-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 1604,17rx,21 trihydroxy 6a methyl-2-oxo-4-pregneno- [3,2-0] pyrazole-16a, Hot-acetonide 21-phosphate.

EXAMPLE 19 Preparation of 6,9a-difiuoro-11 5,1611,17a,21-tetrahydroxy- -oxo 4,6 pregnadieno-[3,2-c]pyrazole-l6a,l7a-acetonide ll-phosphate and sodium salt 0.5 g. of 6,9a-difluoro-115,16a,17a,21-tetrahydroxy20- oxo-4,6-pregnadieno-[3,2-clpyrazole-l6m,Hot-acetonide is added with stirring to 3.0 m1. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room'temperature. The precipitate of 6,9oL-difl11OIO-11,3,16oz,17a,2l-ie'tlahYClIOXY-ZO-OXO- 4,6-pregnadieno-[3,2-c]pyrazole l6ot,17oz acetonide 2lphosphate is removed by filtration and dried under reduced pressure at 100 C.

The 6,9a-difluoro-11 8,16a,1711,2l-tetrahydroxy-ZO-oxo- 4,6-pregnadieno-[3,2-c] pyrazole 16u,l7a acetonide 21- phosphate is dissolved in 50 ml. of Water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 6,9a-difiuoro-11B,16a,17a,21-tetrahydroxy-ZO-oxo 4,6 pregnadieno-[3,2-c]pyrazole 16oz, 17a-acetonide ill-phosphate.

EXAMPLE 20 Preparation of 9oc-fill0I0-1l,3,l6oc,170:,21-t6t121hYd10XY-6- methyl-20-oxo-4,6-pregnadieno-[3,2 c]py1'azole 16oz, I'M-acetonide 21-phosphate and sodium salt 0.5 g. of Qa-flUOIO 11B,16oz,170z,21 tetrahydoxy 6 methyl-20-oxo-4,6-pregnadieno-[3,2-clpyrazole 16a,17uacetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold Water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 9a-fluoro-1l,6,l6a,17a,21-tetrahydroxy-6-methyl-20-oxo-4,6-pregnadieno [3,2-c1pyrazole- 16a,l7a-acetonide ill-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 9a-fluoro-11,8,16m,17a,21-tetrahydroxy-6-methyl-20- oxo-4,6-pregnadieno- [3,2-c1pyrazole-1 60a, 17a acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 9ct-flL1OIO-11fi,l6a,l7oc,2ltetrahydroxy-6-rnethyl-20-oxo-4,6 pregnadieno [3,2-0] pyrazole-16a,17a-acetonide 2l-phosphate.

EXAMPLE 21 Preparation of 9a-fiuoro-115,16a,17a,21-tetrahydroXy-20- 0Xo-2-(p-fiuorophenyl) 4,6-pregnadieno-[3,2-c]pyrazole16a,17a-acetonide ill-phosphate and potassium salt 0.5 g. of 9a-fiuoro-l1B,16a,17u,2l-tetrahydroxy-ZO-oxo- 2(p-fluorophenyl-4,6-pregnadieno [3,2-c1pyrazole 16cc, Not-acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold Water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 9oc-fill0IO11, 3,l6oc,17a,21- tetrahydroxy-20-oXo-2 (p-fluorophenyl) 4,6 pregnadieno-[3,2-c]pyrazole-l6a,l7a-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at C.

The 9a-fluoro-11/3,16a,17u,2l tetrahydroxy-20-oxo-2- (p-fiuorophenyl)-4,6-pregnadieno [3,2-c1pyrazole 16a, Hot-acetonide 2l-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 9afluoro 11fi,16a,17a,2l tetrahydroxy 20 oxo 2' (pfluorophenyl) 4,6 pregnadieno [3,2-c1pyrazole 16a, 17a-acetonide 21-phosphate.

EXAMPLE 22 Preparation of 6-fluoro 16oz,17oc,21 trihydroxy 11,20- dioxo 4,6 pregnadieno [3,2-c1pyrazole 16a,17aacetonide 2l-phosphate and potassium salt 0.5 g. of 6-fluoro-16a,Hall-trihydroxy 11,20-dioxo- 4,6-pregnadieno-[3,2-c1pyrazole 16a,17a acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into ml. of vigorously stirred ice-cold Water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 6-fluoro-l6a,17a,21-trihydroxy-l1,2O dioxo- 4,6-pregnadieno [3,2-c1pyrazole 16a,l7a-acetonide 21- phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 6 fiuoro 16a,17oc,21 trihydroxy 11,20 dioxo- 4,6 pregnadieno[3,2-c]pyrazole 16u,17a-acetonide 21- phosphate is dissolved in 50 ml. of Water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 6-fiuoro-16u,17a,21-trihydroxy 11,20-dioxo 4,6 pregnadieno[3,2-c]pyrazole- 16oz,17oz-3.Ct0r1id6 21-phosphate.

EXAMPLE 23 Preparation of 16oz,17a,21 trihydroxy 6 methyl 11, 20 dioxo 2' phenyl 4,6 pregnadieno [3,2-c] pyrazole-16a,Not-acetonide 2l-phosphate and potassium salt 0.5 g. of 16a,17a,2l-trihydroXy-6-methyl-11,20-dioxo- 2'-phenyl 4,6 pregnadieno [3,2-c[pyrazole 16a,17aacetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously 13 stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 16a,17a,21-trihydoxy-6-methyl-l1, 20 dioxo 2' phenyl 4,6 pregnadiend [3,2-c]pyraz- Ole-16,l7u-acet0nide 2l-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 1601,170 21-trihydroxy-6 methyl.- 1l,20-dioxo-2- phenyl 4,6 pregnadieno [3,2-c]pyrazole 16ot,17aacetonide 2l-phosphate is dissolved in50 ml. of water containingtwo molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 16a, 170:,211' trihydroxy 6 methyl 11,20 dioxo 2'- phenyl 4,6 pregnadieno [3,2-c]pyrazo1e 16u,17aacetonide.

EXAMPLE 24 Preparation of 16a,17ct,21 trihydroxy 11,20 dioxo- 4,6-pregnadieno[3,2 c]pyrazole 16u,17a acetonide 21-phosphate and potassium salt 0.5 g. of.16a,17u,2l-trihydroxy-1l,20-dioxo-4,6-pregnadieno[3,2-c]pyrazole-16m,17a-acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 16a,17a,21-'trihydroxy-1 1,20-dioxo-4,6-pregnadieno 3,2-c] pyrazole-16a,17a-acetonide 2l-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 16a,17u,21-trihydroxy-11,20-dioxo-4,6-pregnadieno [3,2-c]pyrazole-16oz,17a-acetonide 2l-phosphate is dissolved in 50 ml. of Water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 16a,17m,21-trihydroxy-11,20-dioxo-4,6- pregnadieno[3,2-c]pyrazole-16u,17a-acetonide 2l-phos phate.

EXAMPLE 25 Preparation of 16a,17a,2l trihydroxy 11,20 dioxo- 4 pregneno [3,2 cjpyrazole 160:,17u acetonide 2l-phosphate and potassium salt 0.5 g. of l6oz,l7a,21-trihydroxy-l1,20-dioxo-4-pregneno- [3,2-c]pyrazole-16a,l7a-acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature.-The precipitate of 16u,17a,21- trihydroxy 11,20 dioxo 4 pregneno:[3,2-c]pyrazole- 16a,17u-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 160:, l7u,21-trihydroxy-l l,20-dioxo4-pregneno- [3 2-c]pyrazole-16m,17m-acetonide 21-phospl1ate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of 16a,17a,21-trihydroxy-11,20-dioxo-4-pregneno-[3,2-c]pyrazole-16a,17a-acetonide 2l-phosphate.

EXAMPLE 26 Preparation of triamcinolone 21-phosphate and potassium salt 0.5 g. of triamcinolone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addition is complete. The reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The residue is triamcinolone 2l-phosphate in substantially pure form.

The triamcinolone 2l-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of triamcinolone 21-phosphate.

EXAMPLE 27 Preparation of desoxycorticosterone 21-phosphate and potassium salt 0.5 g. of desoxycorticosterone is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture and maintained at 0 C. during addition and for twenty minutes after addition is complete. The reaction mixture is then a clear solution and is slowly added to 100 ml. of vigorously stirred water which is at a temperature of 0 C. The temperature of the mixture is allowed to come to room temperature and extracted three times with 100 ml. portions of chloroform. The chloroform extracts are combined and the chloroform is removed by distillation under reduced pressure. The residue is desoxy- 'corticosterone 21-phosphate in substantially pure form.

The desoxycorticosterone 21-phosphate is dissolved in 50 ml. of water containing two molecular equivalents of potassium hydroxide. The solution is then lyophilized. The resulting white powder is substantially pure dipotassium salt of desoxycorticosterone 21-phosphate.

EXAMPLE 28 Preparation of 3,20 diketo 16a,17a,21 trihydroxy- 4 pregnene l6u,l7a acetonide 21 phosphate and sodium salt 0.5 g. of 3,20-diketo-16a,17u,21-trihydroxy-4-pregnene- 16a,17a-acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 3,20dik6t0-1'6u,l7a,2 l-trihydroxy- 4-pregnene-16a,l7u-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 3,20-diketo-l6a,17ot,21-trihydroxy-4-pregnene-16a, Not-acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 3,20-diketo-16a,l7a, 2l-trihydroxy-4-pregnene-l6a,17u-acetonide 21-phosphate.

EXAMPLE 29 Preparation of 9a-fluoro-1153160;,17a,21-tetrahydroxy-20- oxo 2' (para fiuorophenyl) 4 pregnene [3,2-c] pyrazole 17a acetonide 21 phosphate and sodium salt 0.5 g. of 9oz-flL10IO-l1fl,l6ot,17oz,2I-tCIIahYdIOXY-ZO-OXO- 2 (para fluorophenyl) 4 pregnene [3,2-c]pyrazole- 160:,l7ot-21C6t011ld6 is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 9u-fil10rO-1lfi,l6a,l7a,2ltetrahydroxy 20 oxo 2' (para fiuorophenyl) 4- pregnene [3,2-c]pyrazole 16u,17u acetonide 2l-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The 90: fiuoro 11fi,16oc,17a,21 tetrahydroxy oxo 2' (para-fiuorophenyl) 4 pregnene [3,2-c]pyrazole-16,17a-acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 9afluoro 11,8,16a,l7a,21 tetrahydroxy 2O oxo 2'- (para fluorophenyl) 4 pregnene [3,2-c]pyrazole- 16oc,l7oz-3C6t01lid6 21-phosphate.

EXAMPLE Preparation of l6a,17oc,21 trihydroxy 20 oxo 2- (para fluorophenyl) 4 pregnene [3,2c]pyrazole- 16a,17u-acetonide 2l-ph0Sphate and sodium salt 0.5 g. of 16a,17a,21-trihydroxy-20-oxo-2-(para-fluorophenyl) 4 pregnene [3,2-c]pyrazole 16a,17a-acetonide is added with stirring to 3.0 ml. of pyrophosphoryl chloride which is protected from moisture. The reaction mixture is stirred and maintained at 0 C. during the addition and for thirty minutes after addition is complete and is then poured slowly into 150 ml. of vigorously stirred ice-cold water. Stirring is continued for one hour and the temperature is allowed to rise to room temperature. The precipitate of 16a,1711,2l-trihydroxy-2O-oxo-2'- (para fiuorophenyl) 4 pregnene [3,2-c]pyrazole- 16u,17a-acetonide 21-phosphate is removed by filtration and dried under reduced pressure at 100 C.

The l6oz,17oz,21 trihydroxy 2O 0x0 2' (para-fluorophenyl) 4 pregnene [3,2-c]pyrazole 1607,1707- acetonide 21-phosphate is dissolved in 50 ml. of water containing one molar equivalent of sodium carbonate. The solution is then lyophilized. The resulting white powder is substantially pure disodium salt of 16a,17a,21-trihydroxy 20 oxo 2' (para fluorophenyl) 4 pregnene- [3,2-C1PYI8ZOl6-16ot,170L-3C6t011ld6 21-phosphate.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of the invention.

What is claimed is:

1. The process for preparing a 21-hydroxy-steroid 21- phosphate of the pregnane series which comprises reacting pyrophosphoryl chloride with the corresponding 21- hydroxy-steroid to produce the 21-dichlorophosphate of said 21-hydroxy-steroid, and reacting said 21-hydroxysteroid 21-dichlorophosphate with water.

2. The process as defined in claim 1, in which the starting material is an 11,21-dihydroxy-pregnane steroid, and the product obtained is the corresponding 11,21-dihydroxy-pregnane steroid 21-phosphate.

3. The process as defined in claim 1, in which the starting material is an 11,21-dihydroxy-pregnane steroid having halogen or lower alkyl in the 9-position, and the product is the corresponding 9-(halo or alkyl)-11,21-dihydroxy-pregnane steroid 21-phosphate,

4. The process as defined in claim 1, in which the starting material is a 16,17,21-trihydroxy-pregnane steroid 16, 17-acetonide, and the product obtained is the corresponding 16,17,2l-trihydroxy-pregnane steroid 16,17-acetonide 21-phosphate.

5. The process as defined in claim 1, in which the 21- hydroxy-steroid 21-phosphate product is reacted with an alkali metal hydroxide or alkali metal carbonate to produce the corresponding alkali metal salt of said 21-hydroxy-steroid 21-phosphate. I

6. The process for preparing 9ot-fiLlOI'0-11 3,16a,17ot,21- tetrahydroxy 2O oxo 2 (para fiuorophenyl) 4 pregnane [3,2-c]pyrazole 1611,1707 acetonide 21-phosphate which comprises reacting pyrophosphoryl chloride with 90:. fiuoro 11,8,16oz,17oc,21 tetrahydroxy 20 0x0- 2' (para fiuorophenyl) 4 pregnene [3,2-c]pyrazole 16a,17a-aeet0nide to produce 9a-fluoro-11fi,l6a,l7a,21- tetrahydroxy 20 oxo 2' (para fluorophenyl) 4- pregnene [3,2-c]pyrazole 1607,1704 acetonide 21-dichlorophosphate, and reacting said 9ot-flHOlO-11,B,l6oc,17u, 21 tetrahydroxy 20 oxo 2' (para fluorophenyl)- 4 pregnene [3,2-c1pyrazole 1607,1701 acetonide 21-dichlorophosphate with water.

7. The process for preparing alkali metal salts of 9afiuoro 11B,16 x,17a,21 tetrahydroxy 20 oxo 2'-(parafiuorophenyl) 4 pregnene [3,2-c]pyrazole 16oc,17otacetonide 21-phosphate which comprises reacting pyrophosphoryl chloride with 9a-fluoro-11;S,16a,17a,21-tetrahydroxy 20 oxo 2 (para fluorophenyl) 4 pregnene [3,2-c]pyrazole 1604,1707 acetonide to produce 90; fiuoro 1l,8,l6a,l7ot,2l tetrahydroxy 20 0x0 2'- (para fiuorophenyl) 4 pregnene [3,2-c1pyrazole- 16a,17a-acetonide 21-dichlorophosphatc, reacting the latter compound with water to form 9a-fiuoro-11 3,16a,l7a, 21 tetrahydroxy 20 oxo 2' (para fiuorophenyl)- 4 pregnene [3,2-c]pyrazole 1607,17 acetonide 21- phosphate, and reacting the last-named compound with an alkali metal hydroxide or alkali metal carbonate.

References Cited UNITED STATES PATENTS 3,053,349 9/1962 Fried 260-23955 FOREIGN PATENTS 1,119,278 12/ 1961 Germany.

OTHER REFERENCES Loewenthal, H.: Tetrahedron, 6, 1959, pp. 269-303, p. 300 relied on.

LEWIS GOTTS, Primary Examiner E. G. LOVE, Assistant Examiner US. Cl. X.R. 

